Preserved etherified cyclodextrin derivatives containing liquid aqueous pharmaceutical composition

ABSTRACT

The present invention is directed to a preserved liquid aqueous pharmaceutical composition comprising one or more etherified cyclodextrin derivatives; one or more water-soluble preservatives; preferably selected from the group consisting of sorbic acid or salts thereof, preferably sodium sorbate, potassium sorbate, calcium sorbate; benzoic acid or salts thereof, preferably sodium benzoate; benzalkonium chloride; benzethonium chloride; cetylpyridinium chloride; sodium metabisulfite; sodium acetate; parabenes and salts thereof, preferably methylparabene, ethylparabene, propylparabene, butylparabene, butylparabene sodium; or combinations thereof; and at least one pharmaceutically active compound which is poorly water-soluble, very poorly water-soluble or water-insoluble. The liquid aqueous pharmaceutical composition provides an acceptable solubility of the pharmaceutically active compound, such as pimobendan, in aqueous solution whereby the water-soluble preservatives retain their effectiveness in the presence of the etherified cyclodextrin derivatives allowing the use in an oral administration form.

FIELD OF THE INVENTION

The invention relates to the field of medicine, particularly veterinarymedicine. In particular, the invention relates to a novel preservedliquid aqueous pharmaceutical composition comprising one or moreetherified cyclodextrin derivatives, one or more water-solublepreservatives and at least one pharmaceutically active compound.

BACKGROUND OF THE INVENTION

Cyclodextrins are cyclic oligosaccharides containing six, seven, oreight (α-1,4)-linked D-glucopyranoside units resulting in alpha(α)-,beta(β)- and gamma(γ)-cyclodextrins. In general, cyclodextrins arepharmaceutical excipients that can solubilize various poorly solubledrugs/molecules through the formation of water-soluble drug-cyclodextrincomplexes (Loftsson T et al., Journal of Pharmaceutical Sciences 2012,101 (9): 3019-3032). More specifically, cyclodextrins in aqueoussolution form inclusion complexes with water-insoluble or poorly solubledrugs by taking up the lipophilic moiety of the drug molecule into thecavity of the cyclodextrin, which is hydrophobic (Brewster M E et al.,Advanced Drug Delivery Reviews 2007, 59: 645-666). However,non-inclusion drug-cyclodextrin complexes can also be formed. The higherthe cyclodextrin concentration increases, the higher the formation ofaggregates of cyclodextrin molecules and self-assembled complexes. Afurther aspect with cyclodextrin containing pharmaceutical compositionsis the formation of self-assembled complexes and/or formation ofaggregates (Messner M et al., International Journal of Pharmaceutics2011, 408: 235-247). Excipients that solubilize and stabilize suchaggregates include small ionized molecules such as salts of organicacids and bases.

A substantial problem with pharmaceutical compositions includingcyclodextrins is to produce pharmaceutical compositions which arepreserved against microbial growth. Such preserved compositions areparticularly important for storage of containers containingmultiple-dose compositions. Typical preservatives are relativelyineffective at normal concentrations in such compositions, ascompositions including such preservatives are unable to meet or passstandard preservative efficacy tests (for example USP <51> or Pharm.Eur. 5.1.3. It is believed that the preservative forms a complex withcyclodextrin and consequently is rendered ineffective or has reducedeffectiveness as a preservative. Thus, the preservative loses its fullactivity by complex formation. The formation of these complexes betweenpreservative and cyclodextrin further reduce the solubility of theactive drug substance (Loftsson T et al., Drug Development andIndustrial Pharmacy 1992, 18 (13): 1477-1484).

Certain etherified β-cyclodextrin derivatives are known to improvesolubility of sparingly soluble drugs, see WO 85/02767. However, in WO85/02767 only the use of etherified β-cyclodextrin derivatives up to aconcentration of 10% is described. A molar ratio of drug to etherifiedβ-cyclodextrin derivative of 1:6 to 4:1 was contemplated. The solubilityof flubendazol within the above given ratio was only increased by afactor 30. However, those formulations are not suitable for thepreparation of pharmaceutical compositions comprising substitutedbenzimidazole derivatives, such as pimobendan.

Further prior art is as follows:

-   US 2004/152664 is directed to compositions comprising cyclodextrin    derivatives and prednisolone.-   WO 2004/089418 deals with a fluoroquinolone comprising aqueous    formulations of a pH between 4 and 7.-   EP 1 920 785 discloses a liquid preparation comprising a complex of    pimobendan and cyclodextrin.-   Brewster M E at al. (Advanced Drug Delivery Reviews 2007, 59 (7):    645-666) describe cyclodextrins as pharmaceutical solubilizers.-   Bassani V L et al. (Journal of Inclusion Phenomena and Molecular    Recognition in Chemistry, 1996, 25 (1-3): 149-152) refer to the    enhanced water-solubility of albendazole by    hydroxypropyl-β-cyclodextrin complexation.

The article of Piel G and co-workers (Sciences Techniques et PratiquesSTP Pharma Pratiques 1999, 9 (3): 257-260) is directed to thedevelopment of a parenteral and an oral formulation of albendazole withcyclodextrins.

This enables the development of a pharmaceutical composition forparenteral use but due to the reduced shelf-life of unpreservedcompositions, it does not enable the development of a pharmaceuticalmultiple-dose composition for oral use. Due to the risk of severetolerance problems and also due to concerns by pet-owners thatinflammation in the subcutis following injections is considered to be arisk factor in the development of sarcomas, it is highly desirable todevelop an oral pharmaceutical composition.

Due to some animals' intense sense of taste, it is particularlydifficult to formulate a medication that can be administered orally andwhich the animal accepts resulting in an easy to use medication foranimals, in particular companion animals, such as dogs, cats and horses(sufficiently good palatability).

The objective underlying the present invention is therefore to provide apharmaceutical composition which overcomes the problems of the prior artas described above. Particularly, a pharmaceutical compositioncontaining a sparingly water-soluble pharmaceutical active compound atpalatable pH values (e.g. >pH 3) shall be provided to be administered inadequate form to a subject in need thereof.

SUMMARY OF THE INVENTION

It is therefore provided a preserved liquid aqueous pharmaceuticalcomposition comprising one or more etherified cyclodextrin derivatives;one or more water-soluble preservatives; preferably selected from thegroup consisting of sorbic acid or salts thereof, preferably sodiumsorbate, potassium sorbate, calcium sorbate; benzoic acid or saltsthereof, preferably sodium benzoate; benzalkonium chloride; benzethoniumchloride; cetylpyridinium chloride; sodium metabisulfite; sodiumacetate; parabenes and salts thereof, preferably methylparabene,ethylparabene, propylparabene, butylparabene, butylparabene sodium; orcombinations thereof; more preferably selected from the group of sorbicacid or salts thereof, preferably sodium sorbate, potassium sorbate,calcium sorbate; benzoic acid or salts thereof, preferably sodiumbenzoate; benzalkonium chloride; benzethonium chloride; cetylpyridiniumchloride; sodium metabisulfite; sodium acetate; or combinations thereof;and at least one pharmaceutically active compound which is poorlywater-soluble, very poorly water-soluble or water-insoluble; whereinpreferably the solubility of the at least one pharmaceutically activecompound in water in the range of 15 to 25° C. is defined as follows:the at least one pharmaceutically active compound is poorlywater-soluble if more than 100 mL of water per gram compound have to beused; it is very poorly water-soluble if more than 1000 mL of water pergram compound have to be used; and it is water-insoluble if more than10,000 mL water per gram compound have to be used to solubilize thecompound; and preferably with the proviso that corticosteroids, inparticular prednisolone and its prodrug prednisolone acetate (see US2004/152664), and fluoroquinolones, in particular ciprofloxacin,gatifloxacin, moxifloxacin, sitafloxacin, lomefloxacin, grepafloxacin,gemifloxacin, norfloxacin, ofloxacin, levofloxacin, trovafloxacin andthe like (see WO 2004/089418), are independently from each otherexcluded as pharmaceutically active compound which is poorlywater-soluble, very poorly water-soluble or water-insoluble.

The present invention is also directed to the liquid pharmaceuticalcomposition for use in a method for treating a subject in need of suchtreatment, preferably an animal, in particular a companion animal, evenmore preferred horse, dog or cat, guinea pig, hamster, cattle, goat,sheep, in particular cat or dog, selected from among the indications:heart diseases, particularly a hypertrophic cardiomyopathy, moreparticularly heart failure (HF), congestive heart failure (CHF), acuteCHF, decompensated endocardiosis (DCE), dilated cardiomyopathy (DCM),asymptomatic (occult) CHF, asymptomatic DCM, hypertrophic cardiomyopathy(HCM), restricted cardiomyopathy (RCM), and heart failure due to HCM,RCM, DCM and/or UCM.

It is also disclosed a process for producing the pharmaceuticalcomposition comprising the steps, adding at least one pharmaceuticallyactive compound, one or more etherified cyclodextrin derivatives, one ormore water-soluble preservatives, optionally one or more antioxidantsand optionally at least one water-soluble polymer to water and mixingunder stirring, adjusting the pH value using a pH adjustment agent,wherein preferably the one or more water-soluble preservatives are addedafter the addition of the at least one pharmaceutically active compound.

Subject of the present invention is also a kit of parts that comprises:

-   -   a. a preserved liquid aqueous pharmaceutical composition        according to the present invention; and    -   b. a package leaflet including the information that the        pharmaceutical composition is to be used for the prevention        and/or treatment of a heart disease, preferably heart failure        and/or hypertrophic cardiomyopathy, in a subject in need of such        prevention or treatment.

It is unexpected that the pharmaceutical composition of the presentinvention can overcome the deficiencies of prior art. The liquid aqueouspharmaceutical compositions for oral administration comprising sparinglyor not water-soluble pharmaceutically active compounds, such aspimobendan, known from prior art are usually not suitable due to the lowconcentration of pharmaceutically active compound normally achieved.

A known pharmaceutically active compound is pimobendan(4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-3(2H)-pyridazinone)disclosed in EP 0 008 391, herein incorporated by reference in itsentirety, and having the formula:

Pimobendan is a well-known compound for the treatment of congestiveheart failure (CHF) originating for example from dilated cardiomyopathy(DCM) or decompensated endocardiosis (DCE) in animals, especially dogs(WO 2005/092343). Furthermore, pimobendan is also used for the treatmentof hypertrophic cardiomyopathy in cats (WO 2010/060874). Pimobendan isalso approved as a drug product for cardiovascular treatment of humans.

As already described in EP 0 439 030 and WO 2005/08467, pimobendan drugsubstance is insoluble in water: 1 g drug substance is soluble in morethan 10,000 mL. At pH 7 the solubility of pimobendan is only about 0.1mg per 100 mL.

The solubility of pimobendan in aqueous solutions is depends on the pH.The solubility of pimobendan is significantly higher at pH 1 to 2.5 thanat higher pH values (pH 2 3.0). However, the local tolerance andpalatability as well as the chemical stability of such a formulation arenot acceptable. This is due to the fact that the target dose wouldrequire a drug concentration in solution which can only be achieved by apH of about pH 2.5 and lower. However, the concentration has to besignificantly higher, resulting in a low volume that the animal willhave to swallow, than is possible at pH≧3.0 in simple aqueous solutions.Accordingly, a pimobendan formulation comprising up to 1.5 mg/mL ofpimobendan would need an increase in solubility at pH 7 by a factor ofabout 1000 to 1500, not achieved in prior art formulations for oraladministration up to now.

On the contrary, the preserved liquid aqueous pharmaceuticalcompositions according to the present invention comprising at least onepharmaceutically active compound which is poorly water-soluble, verypoorly water-soluble or water-insoluble with the assistance of one ormore etherified cyclodextrin derivatives provides an acceptablesolubility of the pharmaceutically active compound such as pimobendan inaqueous solution. Thereby, an acceptable concentration of thepharmaceutically active compound is present allowing for use in an oraladministration form.

Further, the one or more water-soluble preservatives present assure anacceptable efficacy of microbial preservation over the required shelflife of the pharmaceutical composition of the present invention.

Furthermore, and unexpectedly, the above water-soluble preservativesretain their effectiveness in the presence of the etherifiedcyclodextrin derivative(s), i.e. the included water-solublepreservatives do have a substantial preserving efficacy in the presenceof cyclodextrin components.

Since the preserved liquid aqueous pharmaceutical compositions accordingto the present invention may be formulated for oral administration thedisadvantageous side effects of parenteral administration such asinflammation in the subcutis following injections may be avoided. Inaddition, the composition does not have to be given by a veterinarian,as is the case for parenteral administration.

Also the palatability if administered to animal patients is found to begood apparently due to a high concentration of well-palatable etherifiedcyclodextrin-derivatives present in the pharmaceutical composition ofthe present invention.

Moreover, the addition of some excipients such as water-soluble polymersand/or antioxidants have been found to be advantageous in order tofurther increase the concentration of the pharmaceutically activecompound to be used and/or to further stabilize the liquidpharmaceutical composition without interfering with the preservativeeffectiveness of the water-soluble preservatives.

DETAILED DESCRIPTION OF THE INVENTION

Before the embodiments of the present invention are described in furtherdetails it shall be noted that as used herein and in the appendedclaims, the singular forms “a”, “an”, and “the” include plural referenceunless the context clearly dictates otherwise.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art to which this invention belongs. All given ranges and valuesmay vary by 1 to 5% unless indicated otherwise or known otherwise by theperson skilled in the art, therefore, the term “about” was usuallyomitted from the description and claims. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, the preferred methods,devices, and materials are now described. All publications mentionedherein are incorporated herein by reference for the purpose ofdescribing and disclosing the substances, excipients, carriers, andmethodologies as reported in the publications which might be used inconnection with the invention. Nothing herein is to be construed as anadmission that the invention is not entitled to antedate such disclosureby virtue of prior invention.

The present invention is based on the surprising unexpected observationthat a pharmaceutical composition comprising one or more etherifiedcyclodextrin derivatives and at least one pharmaceutically activecompound can be preserved, without occurrence of the above describeddeficiencies, in particular that included water-soluble preservatives dohave a substantial preserving efficacy in the presence of cyclodextrincomponents.

According to the present invention a preserved liquid aqueouspharmaceutical composition is provided. The term “aqueous” is to beunderstood in the meaning that the pharmaceutical composition containswater as a solvent, whereby also one or more additional solvents may beoptionally present. According to one preferred embodiments water is theonly solvent of such pharmaceutically composition.

The liquid aqueous pharmaceutical composition comprises at least onepharmaceutically active compound which is poorly water-soluble, verypoorly water-soluble or water-insoluble. According to the EuropeanPharmacopoeia the solubility of a compound in water in the range of 15to 25° C. is defined as follows:

Solvent in mL per gram compound Very readily soluble    <1 Readilysoluble from 1 to 10 Soluble from >10 to 30 Hardly soluble from >30 to100 Poorly soluble from >100 to 1,000 Very poorly soluble from >1,000 to10,000 Water-insoluble >10,000.

Thus, according to the present invention the at least onepharmaceutically active compound is poorly water-soluble, very poorlywater-soluble or water-insoluble. Preferably the at least onepharmaceutically active compound is poorly water-soluble if more than100 mL of water per gram compound have to be used; it is very poorlywater-soluble if more than 1,000 mL of water per gram compound must beused; and it is water-insoluble if more than 10,000 mL water per gramcompound have to be used to solubilize the compound.

The at least one pharmaceutically active compound is preferably abenzimidazole derivative. The benzimidazole derivative is preferably asubstituted benzimidazole. The term “substituted benzimidazole” as usedherein means, but is not limited to thiabendazol, fuberidazol,oxibendazol, parbendazol, cambendazol, mebendazol, fenbendazol,flubendazol, albendazol, oxfendazol, nocodazol, astemisol andpimobendan, pharmaceutically acceptable salts, derivatives, metabolitesor prodrugs thereof. Most preferably, the term benzimidazole derivativeas used herein means pimobendan, or any pharmaceutically acceptablesalts thereof.

In another aspect the at least one pharmaceutically active compound ispreferably an oxicam derivative. The oxicam derivative is preferably asubstituted oxicam. The term “substituted oxicam” as used herein means,but is not limited to ampiroxicam, droxicam, lornoxicam, piroxicam,tenoxicam and meloxicam, pharmaceutically acceptable salts, derivatives,metabolites or prodrugs thereof. Most preferably, the term oxicamderivative as used herein means meloxicam, or any pharmaceuticallyacceptable salts thereof.

In another aspect the at least one pharmaceutically active compound ispreferably an imidazolinone derivative. The imidazolinone derivative ispreferably a substituted imidazolinone. The term “substitutedimidazolinone” as used herein means, but is not limited to1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one(imepitoin), pharmaceutically acceptable salts, derivatives, metabolitesor prodrugs thereof. Most preferably, the term imidazolinone derivativeas used herein means1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one(imepitoin), or any pharmaceutically acceptable salts thereof.

In another aspect the at least one pharmaceutically active compound ispreferably a glucopyranosyl-substituted benzene derivative. Theglucopyranosyl-substituted benzene derivative is preferably asubstituted glucopyranosyl-substituted benzene derivative. The term“substituted glucopyranosyl-substituted benzene derivative” as usedherein means, but is not limited to1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene,pharmaceutically acceptable salts, derivatives, metabolites or prodrugsthereof. Most preferably, the term glucopyranosyl-substituted benzenederivative as used herein means1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene, orany pharmaceutically acceptable form and/or salt thereof, wherein thepharmaceutically acceptable form preferably is a crystalline complexbetween1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene andone or more amino acids, preferably wherein the one or more amino acidsis proline, more preferably L-proline.

The liquid aqueous pharmaceutical composition according to the presentinvention contains the at least one pharmaceutically active compound asdisclosed herein, particularly in form of a substituted benzimidazole,more particularly pimobendan, preferably in the range of from 0.01 g/100mL to 1 g/100 mL, more preferably from 0.05 g/100 mL to 0.5 g/100 mL,most preferably from 0.1 g/100 mL to 0.25 g/100 mL.

Due to the low aqueous solubility of the pharmaceutically activecompound as disclosed herein, preferably a substituted benzimidazole,such as pimobendan, at pH values that are acceptable for an oralpharmaceutical composition, one or more solubilizing excipients need tobe added to the formulation.

In the present invention such solubilizing excipients are one or moreetherified cyclodextrin derivatives.

The liquid aqueous pharmaceutical composition according to the presentinvention contains the one or more etherified cyclodextrin derivativespreferably in the range of from 5 g/100 mL to 40 g/100 mL morepreferably from 10 g/100 mL to 35 g/100 mL, most preferably from 20g/100 mL to 35 g/100 mL per one etherified cyclodextrin derivative.

The term “etherified cyclodextrin derivative” as used herein includesbut is not limited to alpha-, beta- or gamma-cyclodextrin ethers.Preferably the one or more etherified cyclodextrin derivatives as usedherein means etherified β-cyclodextrins, more preferably of the chemicalformula I:

in which the residues R are independently from each other hydroxyalkylgroups and part of the residues R may optionally independently from eachother be alkyl groups. A partially etherified β-cyclodextrin of formulaI is preferably used, in which the residues R are independently fromeach other hydroxyethyl, hydroxypropyl or dihydroxypropyl groups.Optionally, part of the residues R may for instance be methyl or ethylgroups.

The use of partially methylated β-cyclodextrins with 7 to 14 methylgroups in the β-cyclodextrin molecule as they are known from DE 31 18218 does not fall under the present invention.

Partial ethers of β-cyclodextrin comprising only alkyl groups, such asmethyl, ethyl and the like, may be particularly suitable in accordancewith the invention if they have a low degree of substitution, preferablyas defined below of 0.05 to 0.2.

Even more preferably, the one or more etherified cyclodextrinderivatives as used herein are hydroxyethyl-β-cyclodextrin,hydroxypropyl-β-cyclodextrin, dihydroxypropyl-β-cyclodextrin,sulfobutyl-ether-β-cyclodextrin.

Most preferably, the one or more etherified cyclodextrin derivatives asused herein are hydroxypropyl-β-cyclodextrin (HPβCD), referred to ashydroxypropylbetadex in the European Pharmacopoeia.Hydroxypropyl-β-cyclodextrin (HPβCD) of pharmaceutical grade is marketedfor example under the trademark CAVASOL® W7 HP Pharma and can be orderedfrom Wacker, Germany.

Beta-cyclodextrin is a compound with ring structure consisting of 7anhydro glucose units; it is also referred to as cycloheptaamylose. Eachof the 7 glucose rings contains in 2-, 3-, and 6-position three hydroxygroups which may be etherified. In the partially etherified one or moreβ-cyclodextrin derivatives used according to the invention only part ofthese hydroxy groups is etherified with hydroxyalkyl groups andoptionally further with alkyl groups. When etherifying with hydroxyalkylgroups, which can be carried out by reaction with the correspondingalkylene oxides, the degree of substitution is stated as molarsubstitution (MS), viz. in mole alkylene oxide per anhydroglucose unit(compare U.S. Pat. No. 3,459,731, column 4). In the hydroxyalkyl ethersof β-cyclodextrin used in accordance with the invention the molarsubstitution is preferably between 0.05 and 10, more preferably between0.2 and 2. Particularly preferred is a molar substitution of about 0.40to about 1.50. The etherification with alkyl groups may be stateddirectly as degree of substitution (DS) per glucose unit which as statedabove is 3 for complete substitution. Partially etherifiedβ-cyclodextrins are used within the invention which preferably comprisebesides hydroxyalkyl groups also alkyl groups, especially methyl orethyl groups, up to a degree of substitution of 0.05 to 2.0, morepreferably 0.2 to 1.5. Most preferably the degree of substitution withalkyl groups is between about 0.5 and about 1.2.

As solubilizing excipient hydroxypropyl-β-cyclodextrin (HPβCD) showedvery advantageous effects and resulted in the largest increase insolubility of a pharmaceutically active compound to be used such aspimobendan or a pharmaceutically acceptable salt thereof.

To prevent microbial growth in the solution during the in-use period oneor more water-soluble preservatives are added to the liquid aqueouspharmaceutical composition. Therefore, the liquid aqueous pharmaceuticalcomposition of the present invention comprises one or more water-solublepreservatives. The one or more water-soluble preservatives arepreferably selected from the group consisting of sorbic acid or saltsthereof, preferably sodium sorbate, potassium sorbate, calcium sorbate;benzoic acid or salts thereof, preferably sodium benzoate; benzalkoniumchloride; benzethonium chloride; cetylpyridinium chloride; sodiummetabisulfite; sodium acetate; parabenes and salts thereof, preferablymethylparabene, ethylparabene, propylparabene, butylparabene,butylparabene sodium; or combinations thereof. In a more preferredembodiment, the one or more water-soluble preservatives are selectedfrom the group consisting of sorbic acid or salts thereof, preferablysodium sorbate, potassium sorbate, calcium sorbate; benzoic acid orsalts thereof, preferably sodium benzoate; benzalkonium chloride;benzethonium chloride; cetylpyridinium chloride; sodium metabisulfite;sodium acetate; or combinations thereof. Particularly preferred issorbic acid or salts thereof.

The liquid aqueous pharmaceutical composition according to the presentinvention contains the one or more water-soluble preservativespreferably in the range of from 0.05 g/100 mL to 3.0 g/100 mL, morepreferably from 0.10 g/100 mL to 1.0 g/100 mL, most preferably from 0.20g/100 mL to 0.40 g/100 mL.

The above disclosed water-soluble preservatives do not displace thepharmaceutically active compound from the cyclodextrin complex.Furthermore, and unexpectedly, the above water-soluble preservativesretain their effectiveness in the presence of the etherifiedcyclodextrin derivative.

Therefore, the water-soluble preservatives as listed above allow theprovision of a preserved cyclodextrin-containing pharmaceuticalcomposition which is particularly suitable for oral and/or parenteraluse in veterinary medicine, preferably oral use.

Thus, according to one aspect, the present invention relates to apreserved liquid aqueous pharmaceutical composition comprising one ormore etherified cyclodextrin derivatives, one or more water-solublepreservatives and at least one pharmaceutically active compound asdisclosed herein, particularly in form of a substituted benzimidazole,more particularly pimobendan, wherein the one or more etherifiedcyclodextrin derivative is selected from the group consisting of:alpha-, beta-, and/or gamma-cyclodextrin ether.

According to a further aspect, the present invention relates to apreserved liquid aqueous pharmaceutical composition as described above,comprising one or more etherified cyclodextrin derivatives, one or morewater-soluble preservatives and at least one pharmaceutically activecompound as disclosed herein, particularly in form of a substitutedbenzimidazole, more particularly pimobendan, wherein the one or moreetherified cyclodextrin derivative is etherified β-cyclodextrin.Preferably, that etherified β-cyclodextrin ishydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, ordihydroxypropyl-β-cyclodextrin. Even more preferably, that etherifiedβ-cyclodextrin is hydroxypropyl-β-cyclodextrin (HPβCD), referred to ashydroxypropylbetadex in the European Pharmacopoeia.

The preserved liquid aqueous pharmaceutical composition according to thepresent invention may contain one or more excipients. The one or moreexcipients can be selected from the group consisting of an antioxidant,a water-soluble polymer, buffer, pH adjustment agent, colorants ortaste-masking ingredients including flavors.

Preferably at least one water-soluble antioxidant and/or at least onewater-soluble polymer may be used. More preferably, at least onewater-soluble antioxidant and at least one water-soluble polymer areadded as excipients.

In a preferred embodiment, the liquid aqueous pharmaceutical compositionof the present invention further comprises at least one water-solubleantioxidant and/or at least one water-soluble polymer, more preferablyat least one water-soluble antioxidant and at least one water-solublepolymer.

Thus, according to a preferred embodiment the present invention isdirected to a preserved liquid aqueous pharmaceutical compositioncomprising one or more etherified cyclodextrin derivatives, one or morewater-soluble preservatives; preferably selected from the groupconsisting of sorbic acid or salts thereof, preferably sodium sorbate,potassium sorbate, calcium sorbate; benzoic acid or salts thereof,preferably sodium benzoate; benzalkonium chloride; benzethoniumchloride; cetylpyridinium chloride; sodium metabisulfite; sodiumacetate; parabenes and salts thereof, preferably methylparabene,ethylparabene, propylparabene, butylparabene, butylparabene sodium; orcombinations thereof, more preferably selected from the group of sorbicacid or salts thereof, preferably sodium sorbate, potassium sorbate,calcium sorbate; benzoic acid or salts thereof, preferably sodiumbenzoate; benzalkonium chloride; benzethonium chloride; cetylpyridiniumchloride; sodium metabisulfite; sodium acetate; or combinations thereof;at least one pharmaceutically active compound which is poorlywater-soluble, very poorly water-soluble or water-insoluble; preferablywith the proviso that corticosteroids, in particular prednisolone andits prodrug prednisolone acetate (see US 2004/152664), andfluoroquinolones, in particular ciprofloxacin, gatifloxacin,moxifloxacin, sitafloxacin, lomefloxacin, grepafloxacin, gemifloxacin,norfloxacin, ofloxacin, levofloxacin, trovafloxacin and the like (see WO2004/089418), are independently from each other excluded aspharmaceutically active compound which is poorly water-soluble, verypoorly water-soluble or water-insoluble; and at least one water-solubleantioxidant.

According to the invention it is preferred that the liquid aqueouspharmaceutical composition comprises at least one water-solubleantioxidant because a combination of a water-soluble preservative and anantioxidant in order to stabilize the water-soluble preservative isparticularly preferred. Only a small number of antioxidants are knownwhich are water-soluble and come into question, such as free-radicalscavengers, reduction agents and/or chelating agents. Water-solubleantioxidants that can be used comprise ascorbic acid or pharmaceuticallyacceptable salts thereof, particularly sodium ascorbate; citric acid(anhydrous and/or monohydrate) or pharmaceutically acceptable saltsthereof, particularly sodium citrate; erythorbic acid; fumaric acid;malic acid; monothioglycerol; phosphoric acid; sodium metabisulfite;potassium metabisulfite; propionic acid; sodium bisulfite; sodiumsulfite; resveratrol, butylhydroxyanisol, gallate derivatives,particularly propylgallate, or combinations thereof, preferably ascorbicacid or pharmaceutically acceptable salts thereof, citric acid(anhydrous and/or monohydrate) or pharmaceutically acceptable saltsthereof, sodium metabisulfite, or potassium metabisulfite. Particularlypreferred is ascorbic acid or pharmaceutically acceptable salts thereof.

A preservative system comprising one or more water-soluble preservativespreferably in form of an acid or salt thereof and at least onewater-soluble antioxidant has been shown to be particularly efficient inpreserving the above described liquid aqueous pharmaceuticalcompositions without having a negative effect on the concentration ofthe pharmaceutically active compound in the pharmaceutical compositions.Accordingly, in a preferred embodiment, the liquid aqueouspharmaceutically composition of the invention comprises one or morewater-soluble preservatives and at least one water-soluble antioxidant.

It was found that in particular sorbic acid or a salt thereof showsadvantageous characteristics and preserves the liquid aqueouspharmaceutical composition adequately, albeit at a higher concentrationthan in solutions not containing a cyclodextrin. From the viewpoint ofantimicrobial preservation the pH range of 2.5 to 4.5, in particular3.5, is advantageous of (1) being in the acidic range (improvedantimicrobial activity even without a preservative) and (2) being wellbelow the acid dissociation constant (pK_(a)) value of 4.75 for sorbicacid. Only at pH values below pK_(a) most of the sorbic acid is presentin the protonated (uncharged) state, which is necessary for diffusionthrough the cell membrane of bacteria and fungi.

Furthermore, the presence of at least one water-soluble antioxidant hasa positive influence on the pharmaceutical composition of the presentinvention:

The water-soluble antioxidant, preferably ascorbic acid or saltsthereof, was found to chemically stabilize the one or more water-solublepreservatives, for example sorbic acid or salts thereof, in theformulation. Furthermore, the solubility of the one or morewater-soluble preservatives could be increased if at least oneantioxidant was present. Tests showed an increase in solubility ofsorbic acid by about 0.25% (m/V) by the addition of ascorbic acid.

Furthermore, some water-soluble preservatives such as sorbic acid andpotassium sorbate are sensitive to oxidation so that at least oneantioxidant should preferably be added.

Small amounts of antioxidant may have a benefit for the pharmaceuticalcomposition according to the present invention.

In a further aspect the liquid aqueous pharmaceutical compositionaccording to the present invention comprises at least one water-solubleantioxidant preferably in the range of from 0.2 g/100 mL to 2.0 g/100mL, in particular from 0.3 g/100 mL to 1.0 g/100 mL.

In a further aspect the liquid aqueous pharmaceutical compositionaccording to the present invention comprises a ratio of water-solublepreservative and antioxidant preferably being from 0.1 to 10, inparticular from 0.1 to 1.5, most preferably from 0.2 to 0.8.

According to the invention it has been found that the concentration ofthe pharmaceutically active compound that is dissolved with theassistance of one or more etherified cyclodextrin derivatives may befurther increased by the addition of at least one water-soluble polymer.

It has been found that the water-soluble polymer does not influence thepreservative effectiveness. Furthermore, the described formation ofself-assembled complexes and/or formation of aggregates may be furtherreduced or completely prevented by excipients that solubilize andstabilize such aggregates, e.g. water-soluble polymers such as cellulosederivatives.

In addition, inclusion of such water-soluble polymers in the formulationcan be used to optimize the viscosity of the oral solution to easedosing for example from a plastic syringe.

According to the invention the at least one water-soluble polymer haspreferably a molar mass of 5,000 to 500,000 g/mol, more preferably10,000 to 300,000 g/mol, even more preferred 15,000 to 200,000 g/mol,even more preferred 20,000 to 200,000 g/mol. Examples for said watersoluble polymer are hydroxypropyl methylcellulose (hypromellose, HPMC),hydroxypropyl cellulose, carboxymethylcellulose, hydroxyethyl cellulose,hydroxyethylmethyl cellulose, ethylcellulose, methylcellulose,polyvinylpyrrolidone, polyvinylacetate as well as combinations orcopolymers thereof, preferably hydroxypropyl methylcellulose(hypromellose).

The liquid aqueous pharmaceutical composition according to the presentinvention optionally contains the at least one water-soluble polymerpreferably in the range of from 0.01 g/100 mL to 0.75 g/100 mL, morepreferably from 0.02 g/100 mL to 0.50 g/100 mL, most preferably from0.05 g/100 mL to 0.30 g/100 mL.

Thus, according to a preferred embodiment the present invention isdirected to a preserved liquid aqueous pharmaceutical compositioncomprising one or more etherified cyclodextrin derivatives; one or morewater-soluble preservatives; preferably selected from the groupconsisting of sorbic acid or salts thereof, preferably sodium sorbate,potassium sorbate, calcium sorbate; benzoic acid or salts thereof,preferably sodium benzoate; benzalkonium chloride; benzethoniumchloride; cetylpyridinium chloride; sodium metabisulfite; sodiumacetate; parabenes and salts thereof, preferably methylparabene,ethylparabene, propylparabene, butylparabene, butylparabene sodium; orcombinations thereof, more preferably selected from the group consistingof sorbic acid or salts thereof, preferably sodium sorbate, potassiumsorbate, calcium sorbate; benzoic acid or salts thereof, preferablysodium benzoate; benzalkonium chloride; benzethonium chloride;cetylpyridinium chloride; sodium metabisulfite; sodium acetate; orcombinations thereof; at least one pharmaceutically active compoundwhich is poorly water-soluble, very poorly water-soluble orwater-insoluble; preferably with the proviso that corticosteroids, inparticular prednisolone and its prodrug prednisolone acetate (see US2004/152664), and fluoroquinolones, in particular ciprofloxacin,gatifloxacin, moxifloxacin, sitafloxacin, lomefloxacin, grepafloxacin,gemifloxacin, norfloxacin, ofloxacin, levofloxacin, trovafloxacin andthe like (see WO 2004/089418), are independently from each otherexcluded as pharmaceutically active compound which is poorlywater-soluble, very poorly water-soluble or water-insoluble; and atleast one water-soluble polymer.

According to the invention the pH of the pharmaceutical composition fororal use has preferably a pH value of 2 to 10, more preferably 3 to 10,more preferably 3 to 8, more preferably 3.1 to 8, more preferably 3 to7, even more preferably 3.2 to 7, even more preferably 2.5 to 5, mostpreferably 3 to 5. Particularly preferred is pH 3.3 to 6, particularly3.4 to 5, especially 3.4 to 4. By using the lowest preferred, but stillacceptable pH value, it is possible to further increase the solubilityof the pharmaceutically active compound as disclosed herein, such aspimobendan, compared to that at higher pH values. Besides the bettersolubility of the pharmaceutically active compound compared to higher pHvalues, the lower pH value range has the further advantage of improvedpreservative efficacy. An improved preservative efficacy results in alower concentration of a given preservative which is required to achievean adequate preservative effect.

According to a further preferred embodiment the present invention isdirected to a preserved liquid aqueous pharmaceutical compositioncomprising one or more etherified cyclodextrin derivatives; one or morewater-soluble preservatives; preferably selected from the groupconsisting of sorbic acid or salts thereof, preferably sodium sorbate,potassium sorbate, calcium sorbate; benzoic acid or salts thereof,preferably sodium benzoate; benzalkonium chloride; benzethoniumchloride; cetylpyridinium chloride; sodium metabisulfite; sodiumacetate; parabenes and salts thereof, preferably methylparabene,ethylparabene, propylparabene, butylparabene, butylparabene sodium; orcombinations thereof, more preferably selected from the group consistingof sorbic acid or salts thereof, preferably sodium sorbate, potassiumsorbate, calcium sorbate; benzoic acid or salts thereof, preferablysodium benzoate; benzalkonium chloride; benzethonium chloride;cetylpyridinium chloride; sodium metabisulfite; sodium acetate; orcombinations thereof; at least one pharmaceutically active compoundwhich is poorly water-soluble, very poorly water-soluble orwater-insoluble; preferably with the proviso that corticosteroids, inparticular prednisolone and its prodrug prednisolone acetate (see US2004/152664), and fluoroquinolones, in particular ciprofloxacin,gatifloxacin, moxifloxacin, sitafloxacin, lomefloxacin, grepafloxacin,gemifloxacin, norfloxacin, ofloxacin, levofloxacin, trovafloxacin andthe like (see WO 2004/089418), are independently from each otherexcluded as pharmaceutically active compound which is poorlywater-soluble, very poorly water-soluble or water-insoluble; at leastone water-soluble antioxidant; and at least one water-soluble polymer.

According to a further aspect, the present invention relates to a liquidaqueous pharmaceutical composition as described above, comprising atleast one pharmaceutically active compound in the form of at least onesubstituted benzimidazole or a pharmaceutically acceptable salt thereofor a substituted oxicam or a pharmaceutically acceptable salt thereof ora substituted imidazolinone or a pharmaceutically acceptable saltthereof or a substituted glucopyranosyl-substituted benzene derivativeor a pharmaceutically acceptable form and/or salt thereof, one or moreetherified cyclodextrin derivatives in the form of etherifiedβ-cyclodextrin, one or more water-soluble preservatives, optionally atleast one water-soluble polymer and optionally at least onewater-soluble antioxidant.

Therefore, the present invention preferably relates to a liquid aqueouspharmaceutical composition as described above, comprising:

-   -   a. at least one pharmaceutically active compound in the form of        a substituted benzimidazole or a pharmaceutically acceptable        salt thereof, preferably thiabendazol, fuberidazol, oxibendazol,        parbendazol, cambendazol, mebendazol, fenbendazol, flubendazol,        albendazol, oxfendazol, nocodazol, astemisol or pimobendan, or        pharmaceutical acceptable salts thereof, more preferably        pimobendan or a pharmaceutically acceptable salt thereof;    -   b. one or more etherified cyclodextrin derivatives in the form        of etherified β-cyclodextrin, preferably        hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin,        dihydroxypropyl-β-cyclodextrin, more preferably        hydroxypropyl-β-cyclodextrin (HPβCD);    -   c. one or more water-soluble preservatives, preferably selected        from the group consisting of sorbic acid or salts thereof,        benzoic acid or salts thereof, benzalkonium chloride,        benzethonium chloride, cetylpyridinium chloride, sodium        metabisulfite, sodium acetate; parabenes and salts thereof,        preferably methylparabene, ethylparabene, propylparabene,        butylparabene, butylparabene sodium; or combinations thereof,        more preferably selected from the group consisting of sorbic        acid or salts thereof, preferably sodium sorbate, potassium        sorbate, calcium sorbate; benzoic acid or salts thereof,        preferably sodium benzoate; benzalkonium chloride; benzethonium        chloride; cetylpyridinium chloride; sodium metabisulfite; sodium        acetate; or combinations thereof, most preferably sorbic acid or        salts thereof;    -   d. optionally, but according to a preferred embodiment, at least        one water-soluble antioxidant, preferably ascorbic acid or a        salt thereof; citric acid (anhydrous and/or monohydrate) or a        salt thereof; sodium metabisulfite, potassium metabisulfite or        resveratrol; and    -   e. optionally, but according to a preferred embodiment, at least        one water-soluble polymer with a molar mass of 5,000 to 500,000        g/mol, preferably 10,000 to 300,000 g/mol, even more preferred        15,000 to 200,000 g/mol, even more preferred 20,000 to 200,000        g/mol, preferably hydroxypropyl methylcellulose, hydroxypropyl        cellulose, or methylcellulose, more preferably hydroxypropyl        methylcellulose (hypromellose).

Therefore, the present invention preferably relates to a liquid aqueouspharmaceutical composition as described above, comprising:

-   -   a. at least one pharmaceutically active compound in the form of        a substituted oxicam or a pharmaceutically acceptable salt        thereof, preferably ampiroxicam, droxicam, lornoxicam,        piroxicam, tenoxicam and meloxicam, or pharmaceutical acceptable        salts thereof, more preferably meloxicam or a pharmaceutically        acceptable salt thereof;    -   b. one or more etherified cyclodextrin derivatives in the form        of etherified β-cyclodextrin, preferably        hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin,        dihydroxypropyl-β-cyclodextrin, more preferably        hydroxypropyl-β-cyclodextrin (HPβCD);    -   c. one or more water-soluble preservatives, preferably selected        from the group consisting of sorbic acid or salts thereof,        benzoic acid or salts thereof, benzalkonium chloride,        benzethonium chloride, cetylpyridinium chloride, sodium        metabisulfite, sodium acetate; parabenes and salts thereof,        preferably methylparabene, ethylparabene, propylparabene,        butylparabene, butylparabene sodium; or combinations thereof,        more preferably selected from the group consisting of sorbic        acid or salts thereof, preferably sodium sorbate, potassium        sorbate, calcium sorbate; benzoic acid or salts thereof,        preferably sodium benzoate; benzalkonium chloride; benzethonium        chloride; cetylpyridinium chloride; sodium metabisulfite; sodium        acetate; or combinations thereof, most preferably sorbic acid or        salts thereof;    -   d. optionally, but according to a preferred embodiment, at least        one water-soluble antioxidant, preferably ascorbic acid or a        salt thereof; citric acid (anhydrous and/or monohydrate) or a        salt thereof; sodium metabisulfite, potassium metabisulfite or        resveratrol; and    -   e. optionally, but according to a preferred embodiment, at least        one water-soluble polymer with a molar mass of 5,000 to 500,000        g/mol, preferably 10,000 to 300,000 g/mol, even more preferred        15,000 to 200,000 g/mol, even more preferred 20,000 to 200,000        g/mol, preferably hydroxypropyl methylcellulose, hydroxypropyl        cellulose, or methylcellulose, more preferably hydroxypropyl        methylcellulose (hypromellose).

Therefore, the present invention preferably relates to a liquid aqueouspharmaceutical composition as described above, comprising:

-   -   a. at least one pharmaceutically active compound in the form of        a substituted imidazolinone or a pharmaceutically acceptable        salt thereof, preferably        1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one        (imepitoin) or a pharmaceutically acceptable salt thereof;    -   b. one or more etherified cyclodextrin derivatives in the form        of etherified β-cyclodextrin, preferably        hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin,        dihydroxypropyl-β-cyclodextrin, more preferably        hydroxypropyl-β-cyclodextrin (HPβCD);    -   c. one or more water-soluble preservatives, preferably selected        from the group consisting of sorbic acid or salts thereof,        benzoic acid or salts thereof, benzalkonium chloride,        benzethonium chloride, cetylpyridinium chloride, sodium        metabisulfite, sodium acetate; parabenes and salts thereof,        preferably methylparabene, ethylparabene, propylparabene,        butylparabene, butylparabene sodium; or combinations thereof,        more preferably selected from the group consisting of sorbic        acid or salts thereof, preferably sodium sorbate, potassium        sorbate, calcium sorbate; benzoic acid or salts thereof,        preferably sodium benzoate; benzalkonium chloride; benzethonium        chloride; cetylpyridinium chloride; sodium metabisulfite; sodium        acetate; or combinations thereof, most preferably sorbic acid or        salts thereof;    -   d. optionally, but according to a preferred embodiment, at least        one water-soluble antioxidant, preferably ascorbic acid or a        salt thereof; citric acid (anhydrous and/or monohydrate) or a        salt thereof; sodium metabisulfite, potassium metabisulfite or        resveratrol; and    -   e. optionally, but according to a preferred embodiment, at least        one water-soluble polymer with a molar mass of 5,000 to 500,000        g/mol, preferably 10,000 to 300,000 g/mol, even more preferred        15,000 to 200,000 g/mol even more preferred 20,000 to 200,000        g/mol, preferably hydroxypropyl methylcellulose, hydroxypropyl        cellulose, or methylcellulose, more preferably hydroxypropyl        methylcellulose (hypromellose).

Therefore, the present invention preferably relates to a liquid aqueouspharmaceutical composition as described above, comprising:

-   -   a. at least one pharmaceutically active compound in the form of        a substituted glucopyranosyl-substituted benzene derivative or a        pharmaceutically acceptable salt thereof, preferably        1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene,        or pharmaceutical acceptable salts thereof, more preferably        1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene,        or any pharmaceutically acceptable form and/or salt thereof,        wherein the pharmaceutically acceptable form preferably is a        crystalline complex between        1-cyano-2-(4-cyclopropyl-benzyl)-4-(3-D-glucopyranos-1-yl)-benzene        and one or more amino acids, preferably wherein the one or more        amino acids is proline, more preferably L-proline;    -   b. one or more etherified cyclodextrin derivatives in the form        of etherified β-cyclodextrin, preferably        hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin,        dihydroxypropyl-β-cyclodextrin, more preferably        hydroxypropyl-β-cyclodextrin (HPβCD);    -   c. one or more water-soluble preservatives, preferably selected        from the group consisting of sorbic acid or salts thereof,        benzoic acid or salts thereof, benzalkonium chloride,        benzethonium chloride, cetylpyridinium chloride, sodium        metabisulfite, sodium acetate; parabenes and salts thereof,        preferably methylparabene, ethylparabene, propylparabene,        butylparabene, butylparabene sodium; or combinations thereof,        more preferably selected from the group consisting of sorbic        acid or salts thereof, preferably sodium sorbate, potassium        sorbate, calcium sorbate; benzoic acid or salts thereof,        preferably sodium benzoate; benzalkonium chloride; benzethonium        chloride; cetylpyridinium chloride; sodium metabisulfite; sodium        acetate; or combinations thereof, most preferably sorbic acid or        salts thereof;    -   d. optionally, but according to a preferred embodiment, at least        one water-soluble antioxidant, preferably ascorbic acid or a        salt thereof; citric acid (anhydrous and/or monohydrate) or a        salt thereof; sodium metabisulfite, potassium metabisulfite or        resveratrol; and    -   e. optionally, but according to a preferred embodiment, at least        one water-soluble polymer with a molar mass of 5,000 to 500,000        g/mol, preferably 10,000 to 300,000 g/mol, even more preferred        15,000 to 200,000 g/mol, even more preferred 20,000 to 200,000        g/mol, preferably hydroxypropyl methylcellulose, hydroxypropyl        cellulose, or methylcellulose, more preferably hydroxypropyl        methylcellulose (hypromellose).

The liquid aqueous pharmaceutical composition according to the presentinvention preferably comprises:

-   -   a. 0.01 g/100 mL to 1 g/100 mL substituted benzimidazole or a        pharmaceutically acceptable salt thereof, preferably pimobendan        or a pharmaceutically acceptable salt thereof, or a substituted        oxicam or a pharmaceutically acceptable salt thereof, preferably        meloxicam or a pharmaceutically acceptable salt thereof, or a        substituted imidazolinone or a pharmaceutically acceptable salt        thereof, preferably        1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one        (imepitoin) or a pharmaceutically acceptable salt thereof, or a        substituted glucopyranosyl-substituted benzene derivative or a        pharmaceutically acceptable form and/or salt thereof, preferably        1-cyano-2-(4-cyclopropyl-benzyl)-4-(3-D-glucopyranos-1-yl)-benzene,        or any pharmaceutically acceptable form and/or salt thereof,        wherein the pharmaceutically acceptable form preferably is a        crystalline complex between        1-cyano-2-(4-cyclopropyl-benzyl)-4-(3-D-glucopyranos-1-yl)-benzene        and one or more amino acids, preferably wherein the one or more        amino acids is proline, more preferably L-proline;    -   b. 5 g/100 mL to 40 g/100 mL of one or more etherified        cyclodextrin-derivatives, preferably        hydroxypropyl-β-cyclodextrin;    -   c. 0.05 g/100 mL to 3.0 g/100 mL of at least one water-soluble        preservative, preferably sorbic acid or a salt thereof;    -   d. optionally, but according to a preferred embodiment, 0.2        g/100 mL to 2.0 g/100 mL of at least one water-soluble        antioxidant, preferably ascorbic acid or a salt thereof and    -   e. optionally, but according to a preferred embodiment, 0.01        g/100 mL to 0.75 g/100 mL of at least one water-soluble polymer,        preferably hydroxypropyl methylcellulose (hypromellose).

According to another aspect the liquid aqueous pharmaceuticalcomposition according to the present invention preferably comprises:

-   -   a. 0.1 g/100 mL to 0.25 g/100 mL pimobendan or a        pharmaceutically acceptable salt thereof or meloxicam or a        pharmaceutically acceptable salt thereof or        1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one        (imepitoin) or a pharmaceutically acceptable salt thereof or        1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene,        or any pharmaceutically acceptable form and/or salt thereof,        wherein the pharmaceutically acceptable form preferably is a        crystalline complex between        1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene        and one or more amino acids, preferably wherein the one or more        amino acids is proline, more preferably L-proline;    -   b. 20 g/100 mL to 35 g/100 mL of a hydroxypropyl-β-cyclodextrin;    -   c. 0.05 g/100 mL to 0.30 g/100 mL of hydroxypropyl        methylcellulose (hypromellose);    -   d. 0.20 g/100 mL to 0.40 g/100 mL of a water-soluble        preservative, preferably sorbic acid or a salt thereof;    -   e. 0.3 g/100 mL to 1.0 g/100 mL of an antioxidant, preferably        ascorbic acid or a salt thereof;    -   f. wherein optionally the pH of the composition is between 2 to        10, preferably 3 to 10, more preferably 3 to 8, more preferably        3 to 7, more preferably 2.5 to 5, even more preferably 3 to 5,        even more preferably 3.4 to 5 and most preferably 3.4 to 4.

With regard to the palatability if administered to animal patients theliquid aqueous pharmaceutically composition is well accepted.

The liquid aqueous pharmaceutical composition provides an acceptablesolubility of the pharmaceutically active compound as disclosed herein,such as pimobendan in aqueous solution, according to which a minimumconcentration of the pharmaceutically active compound is presentallowing for use in an oral administration form. For example, theminimum concentration of pimobendan is preferably 1.5 mg/mL=0.15% (m/V).Furthermore, there is only a negligible crystal growth of thepharmaceutically active compound, if any, during the storage period.Further, the one or more water-soluble preservatives present assure theacceptable efficacy of microbial preservation. In addition, the chemicallong-term stability of the active ingredient has been found to be goodaccording to an accelerated stability test in the range of 3.0≦pH≦6.0.

The person skilled in the art knows the effective dosage ofpharmaceutically active compounds as disclosed herein, such asbenzimidazole derivatives, in particular pimobendan, and is readily ableto adjust this dosage which is to be administered to the patient such asan animal patient, in need thereof. In order to have a general guidancein this connection a general therapeutic effective target dose, inparticular for the treatment of HCM in cats, is about 0.1 mg to 0.5 mgpimobendan twice daily per kg bodyweight of the animal, preferably about0.3 mg pimobendan twice daily per kg bodyweight of the animal.

The liquid aqueous pharmaceutical composition according to the presentinvention is intended for oral and/or parenteral administration,particularly oral solutions may be provided.

According to a preferred embodiment of the present invention the liquidaqueous pharmaceutical composition comprises the pharmaceutically activecompound in form of a substituted benzimidazole, preferably pimobendan,or a substituted oxicam, preferably meloxicam, or a substitutedimidazolinone, preferably1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one(imepitoin) or a substituted glucopyranosyl-substituted benzenederivative, preferably1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene, orany pharmaceutically acceptable form and/or salt thereof, wherein thepharmaceutically acceptable form preferably is a crystalline complexbetween1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene andone or more amino acids, preferably wherein the one or more amino acidsis proline, more preferably L-proline, in a therapeutically effectiveamount of up to 5 mg/mL, preferably of 1.5 to 4 mg/mL, even morepreferably of 1.5 to 3 mg/mL.

According to a further aspect, the present invention also relates to amethod of treatment and/or prevention of diseases, wherein cardiotonic,hypotensive, anti-inflammatory and anti-thrombotic substances have atherapeutic benefit, preferably directed to a subject suffering fromheart diseases, particularly a hypertrophic cardiomyopathy, comprisingthe step of administering to such subject in need of such treatment atherapeutically effective amount of any of the liquid aqueouspharmaceutical compositions as described herein.

Preferably, the liquid aqueous pharmaceutical composition of the presentinvention is administered in a therapeutically effective amount fromabout 0.075 mg to about 0.5 mg in form of a substituted benzimidazolederivative, preferably pimobendan, or a substituted oxicam, preferablymeloxicam, or a substituted imidazolinone preferably1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one(imepitoin) or a substituted glucopyranosyl-substituted benzenederivative, preferably1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene, orany pharmaceutically acceptable form and/or salt thereof, wherein thepharmaceutically acceptable form preferably is a crystalline complexbetween1-cyano-2-(4-cyclopropyl-benzyl)-4-(3-D-glucopyranos-1-yl)-benzene andone or more amino acids, preferably wherein the one or more amino acidsis proline, more preferably L-proline, per kg bodyweight of the animal,more preferably from about 0.2 mg to about 0.4 mg of thepharmaceutically active compound in form of a substituted benzimidazolederivative, preferably pimobendan, or a substituted oxicam, preferablymeloxicam, or a substituted imidazolinone preferably1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one(imepitoin) or a substituted glucopyranosyl-substituted benzenederivative, preferably1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene, orany pharmaceutically acceptable form and/or salt thereof, wherein thepharmaceutically acceptable form preferably is a crystalline complexbetween1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene andone or more amino acids, preferably wherein the one or more amino acidsis proline, more preferably L-proline, per kg bodyweight of the animal,even more preferably about 0.3 mg of the pharmaceutically activecompound in form of a substituted benzimidazole derivative, preferablypimobendan, or a substituted oxicam, preferably meloxicam, or asubstituted imidazolinone preferably1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one(imepitoin) or a substituted glucopyranosyl-substituted benzenederivative, preferably1-cyano-2-(4-cyclopropyl-benzyl)-4-(3-D-glucopyranos-1-yl)-benzene, orany pharmaceutically acceptable form and/or salt thereof, wherein thepharmaceutically acceptable form preferably is a crystalline complexbetween1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene andone or more amino acids, preferably wherein the one or more amino acidsis proline, more preferably L-proline, twice daily per kg bodyweight ofthe animal. Preferably, two doses are to be administered per day (twicedaily administration).

The subject/patient in need of any such treatment mentioned above is amammal, preferably a companion animal. The term “animal” as used hereinincludes but is not limited to companion animals such as dogs, cats,guinea pigs, hamsters, horses, cattle, goats, sheep or the like.Preferably, the subject in need of such treatment is a dog, horse orcat, most preferably a cat or dog.

The liquid aqueous pharmaceutical composition according to the presentinvention is for use in a method for treating a patient in need of suchtreatment, preferably selected from among the indications: heart failure(HF), congestive heart failure (CHF), acute CHF, decompensatedendocardiosis (DCE), dilated cardiomyopathy (DCM), asymptomatic (occult)CHF, asymptomatic DCM, hypertrophic cardiomyopathy (HCM), restrictedcardiomyopathy (RCM), and heart failure due to HCM, RCM, DCM and/or UCM.

More preferably, the liquid aqueous pharmaceutical composition accordingto the present invention is for use in a method for treating a subjectin need of such treatment, preferably an animal, in particular acompanion animal, even more preferred horse, dog or cat, guinea pig,hamster, cattle, goat, sheep, in particular cat or dog, selected fromamong the indications: heart diseases, particularly a hypertrophiccardiomyopathy, more particularly heart failure (HF), congestive heartfailure (CHF), acute CHF, decompensated endocardiosis (DCE), dilatedcardiomyopathy (DCM), asymptomatic (occult) CHF, asymptomatic DCM,hypertrophic cardiomyopathy (HCM), restricted cardiomyopathy (RCM), andheart failure due to HCM, RCM, DCM and/or UCM.

The present invention is also directed to the use of a liquid aqueouspharmaceutical composition as above defined for preparing apharmaceutical composition for the treatment or prevention of diseasesin a subject in need of such treatment, preferably selected from amongthe above indications.

In a preferred embodiment, the liquid aqueous pharmaceutical compositionas defined above for use in the above mentioned methods is for oraland/or parenteral administration, preferably oral administration.

Also subject of the present invention is a kit of parts that comprises:

-   -   a. a preserved liquid aqueous pharmaceutical composition as        described above; and    -   b. a package leaflet including the information that the        pharmaceutical composition is to be used for the prevention        and/or treatment of a heart disease, preferably heart failure        and/or hypertrophic cardiomyopathy, in a subject in need of such        prevention or treatment.

During the production it has been surprisingly found that it ispreferable that the one or more water-soluble preservatives are addedafter the addition of the at least one pharmaceutically active compoundas disclosed herein. In case the one or more water-soluble preservativesare added to the cyclodextrin mixture before the at least onepharmaceutically active compound, the solution may become turbid. If theone or more water-soluble preservatives are added after the at least onepharmaceutically active compound, the produced solution remains clear.

According to a further aspect, the present invention also relates to amanufacturing process for the production of any of the liquid aqueouspharmaceutical compositions as described herein. A process for producingthe pharmaceutical composition comprises the steps of: adding at leastone pharmaceutically active compound, one or more etherifiedcyclodextrin derivatives, one or more water-soluble preservatives,optionally one or more antioxidants and optionally at least onewater-soluble polymer to water and mixing under stirring, adjusting thepH value using a pH adjustment agent, wherein preferably the one or morewater-soluble preservatives are added after the addition of the at leastone pharmaceutically active compound.

In this regard it should be taken into account that the process ofmanufacturing may be arbitrarily selected from manufacturing processesof liquid pharmaceutical compositions known from prior art unless theone or more water-soluble preservatives are added after the addition ofthe at least one pharmaceutically active compound.

In the following a representative process is described which should notbe construed to limit the present invention.

At first, water is weighed in. Optionally, the at least onewater-soluble polymer is added, preferably in portions, to the waterunder stirring until the at least one water-soluble polymer is dissolvedthereby obtaining a first liquid mixture. Alternatively, the one or moreetherified cyclodextrin derivatives are added to the water understirring thereby obtaining a first liquid mixture. Alternatively andoptionally, the one or more etherified cyclodextrin derivatives areadded to the first liquid mixture containing the at least onewater-soluble polymer under stirring until the one or more etherifiedcyclodextrin derivatives are dissolved thereby obtaining a first liquidmixture. Then, an ultrasonic treatment of such first liquid mixture or,preferably under stirring, may be optionally performed. The obtainedfirst liquid mixture or is incubated at room temperature, preferablywithout stirring, for one or more minutes. Afterwards, the at least onepharmaceutically active compound is added, preferably in portions, understirring until it is dissolved thereby obtaining a second liquidmixture. Subsequently, the one or more water-soluble preservatives areadded, preferably in portions, to the obtained second liquid mixtureunder stirring until they are dissolved thereby obtaining a third liquidmixture. Optionally, one or more antioxidants as well as furtherexcipients, if so desired, are added, preferably in portions, to thethird liquid mixture during stirring thereby obtaining a fourth liquidmixture. Then, an ultrasonic treatment of the fourth liquid mixture,preferably under stirring, is optionally performed. The obtained fourthliquid mixture is incubated at room temperature, preferably withoutstirring, for one or more minutes. Subsequently, the pH value of theobtained fourth liquid mixture is determined and adjusted, if necessary,using a pH adjustment agent to the desired pH value thereby obtainingthe liquid aqueous pharmaceutical composition of the present invention.

The at least one pharmaceutically active compound, one or moreetherified cyclodextrin derivatives, one or more water-solublepreservatives, and one or more antioxidants and at least onewater-soluble polymer are those as already described in detail supra.The pH adjustment agent is preferably hydrochloric acid and/or sodiumhydroxide.

The amounts used depend from the at least one pharmaceutically activecompound used as well as the intended treatment, administration routeand the patient to be treated. The person skilled in the art is readilyable to select and adjust the required amounts by his general knowledge.

The invention described will now be illustrated by figures. However, itis expressly pointed out that the figures are intended solely as anillustration and should not be regarded as restricting the invention.

BRIEF DESCRIPTION OF THE FIGURES

Further advantages, features, characteristics and aspects of the presentinvention arise from the drawings which show as follows:

FIG. 1 a schematic diagram wherein the solubility of pimobendan is shownas a function of preservative, cyclodextrin type and pH value insolutions containing 25% (m/V) cyclodextrin;

FIG. 2 a schematic diagram wherein the solubility of pimobendan is shownas a function of type and concentration of polymer, salt or complexationagent; and

FIG. 3 a schematic diagram wherein the solubility of pimobendan is shownas a function of concentration of hydroxypropyl-β-cyclodextrin andpresence of sodium sorbate and hydroxypropyl methylcellulose (HPMC).

FIG. 1 shows a schematic diagram wherein the solubility of pimobendan isindicated as a function of the water-soluble preservatives benzalkoniumchloride, benzethonium chloride, cetalpyridinium chloride, sorbic acid,sodium sorbate, benzoic acid, and sodium benzoate, respectively. Thelast row of columns represents the reference control, which is therespective solution without preservative (“none”).

Each water-soluble preservative has been used with pH values of 3.5,4.5, 5.5, 7, and 9 in combination with a hydroxypropyl-β-cyclodextrinabbreviated as “β” and each water-soluble preservative has been usedwith pH values of 3.5, 4.5, 5.5, and 7 in combination with ahydroxypropyl-gamma-cyclodextrin abbreviated as “γ”. The solutionscontain 25% (m/V) cyclodextrin. Each column in the diagram shows thedetermined solubility of pimobendan as a function of preservative,cyclodextrin type and pH value.

In FIG. 1 it can be seen that the highest solubility of pimobendanoccurs at pH=3.5. Furthermore, pimobendan is more soluble withhydroxypropyl-β-cyclodextrin than hydroxypropyl-gamma-cyclodextrin. Thehighest pimobendan solubility is achieved with sodium sorbate for whichthe solubility is significantly higher compared with the results of thereference control wherein no preservative is present.

FIG. 2 is a schematic diagram wherein the solubility of pimobendan isshown as a function of type and concentration of polymer, salt orcomplexation agent. In order to determine the degree of complexation,the effect of three different polymers, three different salts and onechelating agent on the solubility of pimobendan was tested.

The pH of the solution was 4.5. Metolose is hydroxypropylmethylcellulose=HPMC=Hypromellose. Klucel ELF is hydroxypropylcellulose=HPC. The number after the chemical name indicates theconcentration of additive in % (m/V).

The consistency of the reference values [e.g. “sodium sorbate” vs.“sodium sorbate (repeated)”] shows that the results are consistentbetween the different trials and serves as a plausibility check.

In FIG. 2 it can be seen that the addition of HPMC results in asignificant increase in the solubility of pimobendan. The addition ofsalts or disodium edetate does not significantly increase the solubilityof pimobendan.

FIG. 3 is a schematic diagram wherein the solubility of pimobendan isshown as a function of concentration of hydroxypropyl-β-cyclodextrin andpresence of sodium sorbate and hydroxypropyl methylcellulose (HPMC).Therefore, in FIG. 3 the effect of sodium sorbate and HPMC on thesolubility of pimobendan was illustrated, and also the effect ofconcentration of hydroxypropyl-β-cyclodextrin on the pimobendansolubility. Concentrations of sodium sorbate of 1.0% (m/V) and of HPMCof 0.1% (m/V) were used. The pH value was set to 4.5 using hydrochloricacid in all solutions.

In FIG. 3 it can be seen that the results confirm that sodium sorbatesignificantly increases the solubility of pimobendan. Furthermore, theresults also confirm that HPMC significantly increases the solubility ofpimobendan. By use of both HPMC and sodium sorbate the solubility ofpimobendan is significantly increased.

The invention described will now be illustrated by Examples. However, itis expressly pointed out that the Examples and description are intendedsolely as an illustration and should not be regarded as restricting theinvention. In the following the invention shall be illustrated in formof exemplary pharmaceutical compositions. However, the present inventionis not limited to the described compositions, but other components,amounts and additives are possible.

EXAMPLES Example 1 Manufacturing Process

In the following Table 1 exemplary pharmaceutical compositions accordingto the present invention are given in detail:

TABLE 1 Exemplary pharmaceutical compositions according to the presentinvention Content Ingredient [g/100 mL] Function Pimobendan 0.15-0.25Pharmaceutically active compound Hydroxypropyl-β- 15-35 Etherifiedcyclodextrin cyclodextrin Hydroxypropyl 0.05-2.5  Water-soluble polymermethylcellulose Sorbic acid and/or 0.1-1.0 Water-soluble preservativepotassium sorbate sodium benzoate sodium metabisulfite Ascorbic acidand/or 0.05-1.0  Antioxidant sodium ascorbate sodium metabisulfitecitric acid sodium citrate Hydrochloric acid 0.1M ad pH 3.1-4.0 pHadjustment Water ad 100 mL Solvent

The production procedure of an exemplary pharmaceutical compositionaccording to the present invention for a single small scale batch (100mL) with a target pH value of 3.5 in form of a general instruction is asfollows:

1. Weigh purified water. Add a magnetic stirrer.2. Weigh hydroxypropyl methylcellulose (HPMC) and add in portions to thepurified water while stirring.3. Weigh hydroxypropyl-β-cyclodextrin into a 100 mL glass bottle and addthe HPMC solution while stirring until the hydroxypropyl-β-cyclodextrinis dissolved.4. Let incubate at room temperature without stirring for 10 minutes.5. Weigh pimobendan and add in portions while stirring until pimobendanis dissolved.6. Weigh sorbic acid and add in portions while stirring until sorbicacid is dissolved.7. Weigh ascorbic acid and optionally free-radical scavengers (e.g. BHAor propyl gallate) and add in portions while stirring and nitrogenatmosphere until ascorbic acid and optionally free-radical scavengersare dissolved.8. Let incubate at room temperature without stirring for 10 minutes.9. Determine pH and, if necessary, adjust to 3.50.

Example 2 Antimicrobial Efficacy

The testing criteria applied are those for evaluation of antimicrobialactivity for oral preparations according to Pharm. Eur. 7 (tests at 14days and 28 days). The acceptance criteria of the Ph. Eur. 7, Method5.1.3 “Efficacy of Antimicrobial Preservation” USP 34, and Method <51>Antimicrobial Effectiveness Testing are listed in the following Table 2.

TABLE 2 Criteria for evaluation of antimicrobial activity for oralpreparations according to Pharm. Eur. 7 and USP 34 Type of Ph. Eur. 7Method 5.1.3. USP 34 Method <51> micro- Logarithmic reduction ofmicroorganisms after organism 14 days 28 days 14 days 28 daysBacteria >3 No increase >1.0 No increase from 14 days¹⁾ from 14 days²⁾Fungi >1 No increase from No increase No increase 14 days¹⁾ from initialfrom initial calc. count²⁾ calc. count²⁾ ¹⁾for Ph. Eur: No increase = noincrease in number ²⁾for USP: No increase = not more than 0.5 log₁₀units higher than reference value

The formulations tested in the trial are shown in the following Table 3.

The following microorganisms were tested: Pseudomonas aeruginosa,Straphylococcus aureus, Escherichia coli, Candida albicans, Aspergillusbrasiliensis, Zygosaccharomyces rouxi.

TABLE 3 Formulation no. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 1920 Components Concentration [g/100 mL] Pimobendan 0.15 HP-β-CD 25 HPMC0.1 Sorbic acid 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.2 0.2 0.4 0.4 — — — —— — — — Calcium — — — — — — — — 0.2 — 0.4 — — — — — — — — — sorbatePotassium — — — — — — — — — 0.2 — 0.4 — — — — — — — — sorbate Sodium — —— — — — — — — — — — 0.2 0.4 0.6 0.8 1.0 0.8 — — benzoate Benzalk. — — —— — — — — — — — — — — — — — — 0.1 0.1 chloride Ascorbic acid  0.05  0.05 0.05  0.05  0.05  0.05  0.05  0.05  0.05  0.05  0.05  0.05 — — — — — 0.05 —  0.05 HCl q.s. ad pH 3.5 Purified ad 100 mL water

In the performed tests the USP 34 Method <51> Criteria as listed inTable 2 were found to be fulfilled for all solutions for allmicroorganisms.

Example 3 Formulation Samples were Produced with Compositions Listed inthe Following Table 4

TABLE 4 Formulation No. 1 2 3 4 5 6 7 8 9 Ingredient Concentration[g/100 mL] Pimobendan — — — — — — — 0.15 0.15 1-cyano-2-(4- 0.1 0.1 0.1— — — — — — cyclopropyl-benzyl)- 4-(β-D- glucopyranos-1-yl)- benzeneL-Proline Imepitoin — — — 0.1 0.1 0.1 Meloxicam — — — — — — 0.1 — —Hydroxypropyl-β- 25   25   25   25   25   25   25   25    25   cyclodextrin Hydroxypropyl — 0.1 0.1 — 0.1 0.1 0.1 0.1  0.1 methylcellulose Sorbic acid 0.3 — 0.3 0.3 — 0.3 0.3 — — Methyl paraben —— — — — — — 0.18 0.18 Propyl paraben — — — — — — — 0.02 0.02 HCl q.s. adpH 3.5 pH 3.5 pH 3.5 pH 3.5 pH 3.5 pH 3.5 pH 3.5 pH 3.5 pH 5.0 Water,purified add 100 mL

The following procedure was used to prepare the samples:

1. Weigh entire amount of water into vessel.2. Weigh entire amount of hydroxypropyl methylcellulose (HPMC) into abeaker and add slowly to stirred water. Stir until fully dissolved.3. Weigh entire amount of Hydroxypropyl-β-cyclodextrin (HPβCD) into abeaker and add slowly to stirred mixture. Stir until fully dissolved.4. Let solution stand at least 10 minutes.5. Weigh entire amount of drug substance into a beaker and add slowly tostirred mixture. Stir until fully dissolved.6. Weigh entire amount of sorbic acid into a beaker and add slowly tostirred mixture. Stir until fully dissolved.7. Let solution stand at least 10 minutes.8. Adjust pH to target value with HCl or NaOH.9. Let solutions stand overnight and re-adjust pH to target value withHCl or NaOH.

The solutions were found to have the following densities andappearances:

TABLE 5 Formulation/Solution Density [g/mL] Appearance 1 1.082 Clear,colorless, no particles 2 1.096 Clear, colorless, no particles 3 1.076Clear, colorless, no particles 4 1.075 Clear, colorless, no particles 51.094 Clear, colorless, no particles 6 1.085 Clear, colorless, noparticles 7 1.074 Clear, light yellow, no particles 8 1.080 Clear,colorless, no particles 9 1.082 Clear, colorless, no particles

TABLE 6 Microbial results for tested solutions: E. coli (bacterium), P.aeruginosa (bacterium) and S. aureus (bacterium). Micro- Colony formingunits/g organism Solution no. Innoc. 7 days 14 days 28 days Escherichiacoli 1 540 000 <100 <100 no data available 2 540 000 7300  500 no dataavailable 3 540 000 <100 <100 no data available 4 540 000 <100 <100 nodata available 5 540 000 48 000   2900 no data available 6 540 000 <100<100 no data available 7 420 000 <100 no data available no dataavailable 8 Test not possible¹⁾ 9 Test not possible¹⁾ Pseudomonas 1 440000 <100 <100 no data available aeruginosa 2 440 000 <100 <100 no dataavailable 3 440 000 <100 <100 no data available 4 440 000 <100 <100 nodata available 5 440 000 ²⁾ 16 000   no data available 6 440 000 <100<100 no data available 7 500 000 <100 no data available no dataavailable 8 Test not possible¹⁾ 9 Test not possible¹⁾ Staphylococcus 1350 000 <100 <100 no data available aureus 2 350 000 <100 <100 no dataavailable 3 350 000 <100 <100 no data available 4 350 000 <100 <100 nodata available 5 350 000 <100 <100 no data available 6 350 000 <100 <100no data available 7 320 000 <100 no data available no data available 8Test not possible¹⁾ 9 Test not possible¹⁾ ¹⁾Test could not be starteddue to rapid microbial growth between filtration and start of test²⁾Result not reliable due to high count

TABLE 7 Microbial results for tested solutions: Z. rouxii (yeastfungus), C. albicans (yeast fungus) and A. brasiliensis (mold fungus).Micro- Colony forming units/g organism Solution no. Innoc. 7 days 14days 28 days Candida 1 380 000 <100 <100 no data available albicans 2380 000 530 000   790 000   no data available 3 380 000 <100 <100 nodata available 4 380 000 <100 <100 no data available 5 380 000 500 000  660 000   no data available 6 380 000 <100 <100 no data available 7 370000 <100 no data available no data available 8 Test not possible¹⁾ 9Test not possible¹⁾ Aspergillus 1 120 000 <100  100 no data availablebrasiliensis 2 120 000 290 000   190 000   no data available 3 120 0007800 <100 no data available 4 120 000 10 000    600 no data available 5120 000 830 0000    740 000   no data available 6 120 000 3000  700 nodata available 7 290 000  600 no data available no data available 8 Testnot possible¹⁾ 9 Test not possible¹⁾ ¹⁾Test could not be started due torapid microbial growth between filtration and start of test

It is seen from the results in Table 6 and 7 that a good antimicrobialefficacy is achieved through the use of sorbic acid as a water-solublepreservative. The solutions (no. 2 and 5) with no water-solublepreservative fail the criteria for evaluation of antimicrobial activityaccording to Ph. Eur. The solutions with methyl paraben and propylparaben (no. 8 and 9) had such a high microbial growth that the test ofantimicrobial efficacy was not possible.

Example 4 Small Amounts of Antioxidant, for Example Ascorbic Acid,Surprisingly Provided an Improvement of the Efficacy of MicrobialPreservation

TABLE 8 Formulation compositions in test of efficacy of microbialpreservation. Formulation no. 1 2 3 4 Ingredient Concentration [g/100mL] Pimobendan 0.15 0.15 0.15 0.15 Hydroxypropyl-β- 25 25 25 25cyclodextrin Hydroxypropyl 0.1 0.1 0.1 0.1 methylcellulose Sorbic acid0.3 0.3 0.3 0.3 Ascorbic acid 0.20 0.35 0.50 0.70 HCl q.s. ad pH 3.5 pH3.5 pH 3.5 pH 3.5 Water, purified ad 100 mL

TABLE 9 Microbiological results according to Pharm. Eur. Method 2.6.12.for the fungi Zygosaccharomyces rouxii, Candida albicans and Aspergillusbrasiliensis with varying concentrations of ascorbic acid. Formulationno./incubation period (days) 1 2 3 4 28 28 28 14 28 Micro-organism 14 dd 14 d d 14 d d d d Zygosaccharomyces rouxii a a a a a a a a Candidaalbicans b a a a a a a a Aspergillus brasiliensis c c c b b b b a Codes:a: <LOQ CFU/mL, b: LOQ - 1000 CFU/mL, c: >1000-10 000 CFU/mL, where CFU= colony forming units and LOQ = limit of quantification

The above results demonstrate the increasing efficacy of preservationwith increasing concentration of antioxidant, such as ascorbic acid.

Example 5

The formulations according to EP 1 920 785, paragraph [0067] wereproduced (see table 10).

TABLE 10 mg/10 ml Material Formulation #1 Formulation #2 Pimobendan 10.07.5 Kleptose HP (HP 3300.0 3000.0 Disodium hydrogen phosphate 17.6 17.6dodecahydrate Sodium dihydogen phosphate dihydrate 8.0 8.0 Methylparaben 20.0 10.0 Propyl paraben 5.0 5.0 Disodium edetate 5.0 5.0 Waterfor injection q.s. to 10 ml q.s. to 10 ml

Both formulations were clear, colorless and showed no particles.Formulation #1 has a measured pH of 8.2. Formulation #2 has a measuredpH of 7.6.

What is claimed is:
 1. A preserved liquid aqueous pharmaceuticalcomposition comprising: a. one or more etherified cyclodextrinderivatives; b. one or more water-soluble preservatives; preferablyselected from the group consisting of sorbic acid or salts thereof,preferably sodium sorbate, potassium sorbate, calcium sorbate; benzoicacid or salts thereof, preferably sodium benzoate; benzalkoniumchloride; benzethonium chloride; cetylpyridinium chloride; sodiummetabisulfite; sodium acetate; parabenes and salts thereof, preferablymethylparabene, ethylparabene, propylparabene, butylparabene,butylparabene sodium; or combinations thereof; more preferably selectedfrom the group consisting of sorbic acid or salts thereof, preferablysodium sorbate, potassium sorbate, calcium sorbate; benzoic acid orsalts thereof, preferably sodium benzoate; benzalkonium chloride;benzethonium chloride; cetylpyridinium chloride; sodium metabisulfite;sodium acetate; or combinations thereof; and c. at least onepharmaceutically active compound which is poorly water-soluble, verypoorly water-soluble or water-insoluble, wherein preferably thesolubility of the at least one pharmaceutically active compound in waterin the range of 15 to 25° C. is defined as follows: i. the at least onepharmaceutically active compound is poorly water-soluble if more than100 mL of water per gram compound have to be used; it is very poorlywater-soluble if more than 1,000 mL of water per gram compound have tobe used; and it is water-insoluble if more than 10,000 mL water per gramcompound has to be used to solubilize the compound, and ii. preferablywith the proviso that corticosteroids, in particular prednisolone andits prodrug prednisolone acetate, and fluoroquinolones, in particularciprofloxacin, gatifloxacin, moxifloxacin, sitafloxacin, lomefloxacin,grepafloxacin, gemifloxacin, norfloxacin, ofloxacin, levofloxacin andtrovafloxacin, are independently from each other excluded aspharmaceutically active compound which is poorly water-soluble, verypoorly water-soluble or water-insoluble.
 2. The liquid pharmaceuticalcomposition according to claim 1, wherein the pharmaceutical compositionfurther comprises at least one water-soluble antioxidant, which ispreferably selected from the group consisting of ascorbic acid orpharmaceutically acceptable salts thereof, particularly sodiumascorbate; citric acid (anhydrous and/or monohydrate) orpharmaceutically acceptable salts thereof, more preferably sodiumcitrate; erythorbic acid; fumaric acid; malic acid; monothioglycerol;phosphoric acid; sodium metabisulfite; potassium metabisulfite;propionic acid; sodium bisulfite; sodium sulfite; resveratrol,butylhydroxyanisol, gallate derivatives, particularly propylgallate, orcombinations thereof, most preferably ascorbic acid or pharmaceuticallyacceptable salts thereof, citric acid (anhydrous and/or monohydrate) orpharmaceutically acceptable salts thereof, sodium metabisulfite, orpotassium metabisulfite.
 3. The liquid pharmaceutical compositionaccording to claim 1, wherein the pharmaceutical composition furthercomprises at least one water-soluble polymer, preferably at least onewater-soluble polymer and at least one water-soluble antioxidant.
 4. Theliquid pharmaceutical composition according to claim 1, wherein the oneor more etherified cyclodextrin derivatives are selected from the groupconsisting of: alpha-, beta-, and gamma-cyclodextrin ethers, preferablyetherified β-cyclodextrin having the chemical formula I

in which the residues R are independently from each other hydroxyalkylgroups and part of the residues R may optionally independently from eachother be alkyl groups.
 5. The liquid pharmaceutical compositionaccording to claim 1, wherein the one or more etherified cyclodextrinderivative is hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin,dihydroxypropyl-β-cyclodextrin, sulphobutyl ether-β-cyclodextrin,preferably hydroxypropyl-β-cyclodextrin.
 6. The liquid pharmaceuticalcomposition according to claim 3, wherein the at least one water-solublepolymer is selected from hydroxypropyl methylcellulose (hypromellose,HPMC), hydroxypropyl cellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxyethylmethyl cellulose, ethylcellulose,methylcellulose, polyvinylpyrrolidone, polyvinylacetate as well ascombinations or copolymers thereof, preferably hydroxypropylmethylcellulose (hypromellose).
 7. The liquid pharmaceutical compositionaccording to claim 1, wherein the at least one pharmaceutically activecompound is selected from: a. benzimidazole derivatives, preferablysubstituted benzimidazole derivatives, more preferably thiabendazol,fuberidazol, oxibendazol, parbendazol, cambendazol, mebendazol,fenbendazol, flubendazol, albendazol, oxfendazol, nocodazol, astemisoland pimobendan, pharmaceutically acceptable salts, derivatives,metabolites or pro-drugs thereof, most preferably pimobendan andpharmaceutically acceptable salts thereof; or b. oxicam derivatives,preferably substituted oxicam derivatives, more preferably ampiroxicam,droxicam, lornoxicam, piroxicam, tenoxicam and meloxicam,pharmaceutically acceptable salts, derivatives, metabolites or pro-drugsthereof, most preferably meloxicam and pharmaceutically acceptable saltsthereof; or c. imidazolinone derivatives, preferably substitutedimidazolinone derivatives, more preferably1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one(imepitoin), pharmaceutically acceptable salts, derivatives, metabolitesor pro-drugs thereof, most preferably1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one(imepitoin) and pharmaceutically acceptable salts thereof; or d.glucopyranosyl-substituted benzene derivatives, preferably substitutedglucopyranosyl-substituted benzene derivatives, more preferably1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene, orany pharmaceutically acceptable form and/or salt thereof, wherein thepharmaceutically acceptable form preferably is a crystalline complexbetween1-cyano-2-(4-cyclopropyl-benzyl)-4-(3-D-glucopyranos-1-yl)-benzene andone or more amino acids, preferably wherein the one or more amino acidsis proline, more preferably L-proline.
 8. The liquid pharmaceuticalcomposition according to claim 1, wherein the composition contains theone or more water-soluble preservatives in the range of from 0.05 g/100mL to 3.0 g/100 mL, more preferably from 0.10 g/100 mL to 1.0 g/100 mL,most preferably from 0.20 g/100 mL to 0.40 g/100 mL.
 9. The liquidpharmaceutical composition according to claim 2, wherein the ratio ofwater-soluble preservative and antioxidant is from 0.1 to 10, inparticular from 0.1 to 1.5, most preferably from 0.2 to 0.8.
 10. Theliquid pharmaceutical composition according to claim 3, comprising: a.at least one pharmaceutically active compound in the form of asubstituted benzimidazole or a pharmaceutically acceptable salt thereof,preferably thiabendazol, fuberidazol, oxibendazol, parbendazol,cambendazol, mebendazol, fenbendazol, flubendazol, albendazol,oxfendazol, nocodazol, astemisol or pimobendan, or pharmaceuticallyacceptable salts thereof, more preferably pimobendan or apharmaceutically acceptable salt thereof; or in the form of asubstituted oxicam or a pharmaceutically acceptable salt thereof,preferably ampiroxicam, droxicam, lornoxicam, piroxicam, tenoxicam andmeloxicam, or pharmaceutical acceptable salts thereof, more preferablymeloxicam or a pharmaceutically acceptable salt thereof; or in the formof a substituted imidazolinone or a pharmaceutically acceptable saltthereof, preferably1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one(imepitoin) or a pharmaceutically acceptable salt thereof; or in theform of a substituted glucopyranosyl-substituted benzene derivative or apharmaceutically acceptable salt thereof, preferably1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene, orany pharmaceutically acceptable form and/or salt thereof, wherein thepharmaceutically acceptable form preferably is a crystalline complexbetween1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene andone or more amino acids, preferably wherein the one or more amino acidsis proline, more preferably L-proline; b. one or more etherifiedcyclodextrin derivative in the form of an etherified β-cyclodextrin,preferably hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin,dihydroxypropyl-β-cyclodextrin, more preferablyhydroxypropyl-β-cyclodextrin (HPβCD); c. one or more water-solublepreservatives, preferably selected from the group consisting of sorbicacid or salts thereof, benzoic acid or salts thereof, benzalkoniumchloride, benzethonium chloride, cetylpyridinium chloride, sodiummetabisulfite, sodium acetate; parabenes and salts thereof, preferablymethylparabene, ethylparabene, propylparabene, butylparabene,butylparabene sodium; or combinations thereof, more preferably selectedfrom the group consisting of sorbic acid or salts thereof, benzoic acidor salts thereof, benzalkonium chloride, benzethonium chloride,cetylpyridinium chloride, sodium metabisulfite, sodium acetate; orcombinations thereof, most preferably sorbic acid or salts thereof; d.optionally at least one water-soluble antioxidant, preferably ascorbicacid or a pharmaceutically acceptable salt thereof; citric acid(anhydrous and/or monohydrate) or a pharmaceutically acceptable saltthereof; sodium metabisulfite, potassium metabisulfite or resveratrol;and e. optionally at least one water-soluble polymer with a molar massof 5,000 to 500,000 g/mol, preferably 10,000 to 300,000 g/mol, even morepreferred 15,000 to 200,000 g/mol, even more preferred 20,000 to 200,000g/mol, preferably hydroxypropyl methylcellulose, hydroxypropylcellulose, or methylcellulose, more preferably hydroxypropylmethylcellulose (hypromellose).
 11. The liquid pharmaceuticalcomposition according to claim 3, wherein the composition comprises: a.0.1 g/100 mL to 0.25 g/100 mL pimobendan or a pharmaceuticallyacceptable salt thereof; or meloxicam or a pharmaceutically acceptablesalt thereof; or1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one(imepitoin) or a pharmaceutically acceptable salt thereof; or1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene, orany pharmaceutically acceptable form and/or salt thereof, wherein thepharmaceutically acceptable form preferably is a crystalline complexbetween1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene andone or more amino acids, preferably wherein the one or more amino acidsis proline, more preferably L-proline; b. 20 g/100 mL to 35 g/100 mL ofa hydroxypropyl-β-cyclodextrin; c. 0.05 g/100 mL to 0.30 g/100 mL ofhydroxypropyl methylcellulose (hypromellose); d. 0.20 g/100 mL to 0.40g/100 mL of a water-soluble preservative, preferably sorbic acid or asalt thereof; and e. 0.3 g/100 mL to 1.0 g/100 mL of an antioxidant,preferably ascorbic acid or a salt thereof.
 12. The liquidpharmaceutical composition according to claim 1, wherein the pH of thecomposition is between 2 to 10, preferably 3 to 10, more preferably 3 to8, more preferably 3 to 7, more preferably 2.5 to 5, even morepreferably 3 to 5, even more preferably 3.4 to 5 and most preferably 3.4to
 4. 13. The liquid pharmaceutical composition according to claim 1,wherein the composition is for oral and/or parenteral administration,preferably oral administration.
 14. The liquid pharmaceuticalcomposition according to claim 1, for use in a method for treating asubject in need of such treatment, preferably an animal, in particular acompanion animal, even more preferred horse, dog or cat, guinea pig,hamster, cattle, goat, sheep, in particular cat or dog, selected fromamong the indications: heart diseases, particularly a hypertrophiccardiomyopathy, more particularly heart failure (HF), congestive heartfailure (CHF), acute CHF, decompensated endocardiosis (DCE), dilatedcardiomyopathy (DCM), asymptomatic (occult) CHF, asymptomatic DCM,hypertrophic cardiomyopathy (HCM), restricted cardiomyopathy (RCM), andheart failure due to HCM, RCM, DCM and/or UCM.
 15. A process forproducing the pharmaceutical composition according to claim 1,comprising the steps: a. adding at least one pharmaceutically activecompound, one or more etherified cyclodextrin derivatives, one or morewater-soluble preservatives, optionally one or more antioxidants andoptionally at least one water-soluble polymer to water and mixing whilestirring; and b. adjusting the pH value using a pH adjustment agent;wherein preferably the one or more water-soluble preservatives are addedafter the addition of the at least one pharmaceutically active compound.16. A kit of parts comprising: a. a preserved liquid aqueouspharmaceutical composition according claim 1; and b. a package leafletincluding the information that the pharmaceutical composition is to beused for the prevention and/or treatment of a heart disease, preferablyheart failure and/or hypertrophic cardiomyopathy, in a subject in needof such prevention or treatment.